Treatment or prevention of Crohn&#39;s disease and/or ulcerative colitis

ABSTRACT

The present invention provides a method for the treatment or prevention of Crohn&#39;s disease and/or ulcerative colitis. The method involves the administration of Peptide T or its derivatives or analogues. Preferred compounds used in the method include: 
     1. D--Ala--Ser--Thr--Thr--Thr--Asn--Tyr--Thr--NH 2   
     2. Ala--Ser--Thr--Thr--Thr--Asn--Tyr--Thr 
     3. D--Ala--Ser--Thr--Thr--Thr--Ans--Tyr--Thr 
     4. D--Ala--Ala--Ser--Ser--Ser--Asn--Tyr--Met 
     5. Thr--Asp--Asn--Tyr--Thr 
     6. Thr--Thr--Ser--Tyr--Thr 
     7. Thr--Thr--Asn--Tyr--Thr 
     8. D--Thr--Thr--Tyr--D--Thr 
     9. D--Ala--Ser--D--Thr--Thr--D--Thr--Asn--Tyr--D--Thr--NH 2   
     10. D--Ser--Ser--D--Thr--Thr--D--Thr--Thr--Tyr--D--Thr--NH 2

The present invention relates to the treatment or prevention of Crohn'sDisease and/or ulcerative colitis.

BACKGROUND OF THE INVENTION

Crohn's Disease, or Regional Ileitis, is the term applied to a conditionin which there is an inflammation of an area of the small intestine.This is usually accompanied by colicky abdominal pain, irregularity ofthe bowels, loss of weight and slight fever. The abdomen is generallydistended and the thickened intestine may be felt. The narrowedintestinal canal may become obstructed, necessitating immediateoperation. The cause of the disease is unknown. The primary lesion ishyperplasia of the lymph tissue in the submucosa of the intestine and inthe lymph glands.

As the cause is not known, there is as yet no specific treatment. In theearly stages, current treatment (or at least management) is medical,including a high-vitamin, low-residue diet, sulphonamides andantibiotics. Promising results have been reported from the use ofcorticosteroids in some cases. Operation, consisting of removal of thedamaged section of gut, is reserved for cases which do not respond tomedical treatment. Even in cases apparently successfully operated on,recurrence tends to occur in 15 percent or more of cases.

Short of surgery, therefore, corticosteroid therapy is to date the mostsuccessful remedial treatment for Crohn's Disease. However, steroidchemotherapy is not without its drawbacks and hazards. Goodman andGilman state, in "The Pharmacological Basis of Therapeutics", SeventhEdition, 1985:

"In clinical terms, the administration of corticosteroids for theiranti-inflammatory effects is palliative therapy; the underlying cause ofthe disease remains; the inflammatory manifestations are merelysuppressed. It is this suppression of inflammation and its consequencethat has made the corticosteroids such valuable therapeuticagents--indeed, at times lifesaving. It is also this property that givesthem a nearly unique potential for therapeutic disaster."

Crohn's Disease is a chronic condition of the gastrointestinal tract andinfects most commonly the ileum, colon or a combination of both. It isdistinguished from ulcerative colitis by a differential diagnosis:

Crohn's Disease

Acute appendicitis

Yersinia infection

Lymphoma

Ulcerative jejunoileitis

Colitis

Infective colitis

Ischaemic colitis

Radiation colitis

Other causes of bleeding, e.g. colonic polyps or carcinoma.

DESCRIPTION OF THE INVENTION

It has now been discovered that a group of non-steroidal compounds,namely peptide T and its derivatives and analogues, are useful in theprevention and treatment of Crohn's Disease and/or ulcerative colitis.

Originally, many of the peptides useful in the invention were describedas being effective in the prevention of infection and replication of HIVin vitro, see EP-A-0249390, EP-A-0249394 and WO-A-8809338, all of whichare incorporated by reference to the maximum extent allowed by law, asare all other documents referred to in this specification. The compoundsuseful in the invention are also the subject of pending and as yetunpublished PCT patent application No. PCT/GB93/00649, filed 29 Mar.1993. All compounds disclosed in these specifications are useful for thepresent invention. The original peptide has its basic point of origin inthe octapeptide Ala--Ser--Thr--Thr--Thr--Asn--Tyr--Thr (SEQ ID NO: 1) Itis called Peptide T because 50% of the amino acid residues arethreonine.

Accordingly in a first aspect the present invention, consists in amethod of treating or preventing Crohn's Disease and/or ulcerativecolitis in a subject comprising administering to the subject atherapeutic amount of a linear or cyclic peptide of General Formula 1:

I--A--B--C--D--E--F--G--H--II (General Formula 1) (SEQ ID NO: 2)

wherein A is Ala, Gly, Val, Ser, Thr or absent,

B is Ala, Gly, Val, Ser, Thr or absent

C is Ser, Thr or absent,

D is Ser, Thr, Asn, Glu, Arg, Ile, Leu or absent,

E is Ser, Thr, Asp or absent,

F is Thr, Ser, Asn, Arg, Gln, Lys, Trp or absent,

G is Tyr, Phe, Trp, Leu, Met, Ile or absent,

H is Thr, Arg, Gly, Met, Met(O), Cys, Thr, Gly or absent,

I is Cys or absent,

II is Cys or absent,

at least one of the amino acids optionally being substituted by amonomeric or polymeric carbohydrate or derivative thereof, suchsubstitution being accomplished through hydroxyl and/or amino and/oramido groups of the amino acids,

and wherein the peptide comprises at least four amino acid residues,

or a pharmaceutically acceptable salt thereof.

Each of the amino acids referred to in General Formula 1 may be in theL- or D-stereoisomeric configuration and candidates for H may beesterified or amidated. The peptide comprises at least 4 amino acids.

Tetra-, penta-, hexa-, hepta-, octa- and non-peptides useful in theinvention are all of the peptides chosen from the sequence:

    I--A--B--C--D--E--F--G--H--II

by deleting residues, for example, one at a time, from either thecarboxyl or amino terminal, or from within the sequence.

It is appreciated that peptides having the core sequence of theThr--Thr--Asn--Tyr--Thr-- (SEQ ID NO: 3) may have at both endsadditional amino acid residues, some of which are represented by GeneralFormula 2:

    X--Ser--Thr--Thr--Thr--Asn--Tyr--Y (General Formula 2) (SEQ ID NO: 4)

wherein X is an amino acid terminal residue selected from Ala and D-Alaand Y is a carboxy terminal residue selected from Met, Thr andThr-amide.

A particular preferred peptide of the group of peptides has theaforementioned core sequence of --Thr--Thr--Asn--Tyr--Thr--. Thesepeptides of the above General Formula 2, and in particular a variantPeptide T of the formula --Ser--Thr--Thr--Thr--Asn--Tyr--(SEQ ID NO: 5),were found to be very useful in inhibiting binding of the humanimmunodeficiency virus (HIV) to human cells by blocking receptor siteson the cell surfaces. The term Peptide T is used throughout thespecification to reference, unless the context otherwise requirespeptides of General Formula 2 which all include the core peptidesequence. It is therefore intended that Peptide T encompass all of thecompounds of General Formula 2 where it is understood that all suchcompounds are variants of the normally understood octapeptide T, alsoreferred to as prototype Peptide T, of the particular formulaD--Ala--Ser--Thr--Thr--Thr--Asn--Tyr--Thr--amide.

The invention may be useful in both clinical (human) and veterinarymedicine. The invention therefore has application in a method fortreating or preventing Crohn's Disease and/or ulcerative colitis, themethod comprising administering to a human or other animal subject, forexample on a repeated basis, a peptide of General Formula 1. The peptidewill generally be administered in an effective, non-toxic amount or insuch an amount that strikes an acceptable balance between efficacy andtoxicity, having regard to the circumstances of the case.

Preferred peptides useful in the invention have as their active portion,an amino acid sequence of the formula:

    --Thr--Thr--Asn--Tyr--Thr--

Most preferred peptides useful in the invention are the following:

1. D--Ala--Ser--Thr--Thr--Thr--Asn--Tyr--Thr--NH₂ (prototype Peptide T)

2. Ala--Ser--Thr--Thr--Thr--Asn--Tyr--Thr (SEQ ID NO: 6)

3. D--Ala--Ser--Thr--Thr--Thr--Asn--Tyr--Thr

4. D--Ala--Ala--Ser--Ser--Ser--Asn--Tyr--Met

5. Thr--Asp--Asn--Tyr--Thr (SEQ ID NO: 7)

6. Thr--Thr--Ser--Tyr--Thr (SEQ ID NO: 8)

7. Thr--Thr--Asn--Tyr--Thr

8. D--Thr--Thr--Tyr--D--Thr

9. D--Ala--Ser--D--Thr--Thr--D--Thr--Asn--Tyr--D--Thr--NH₂

10. D--Ser--Ser--D--Thr--Thr--D--Thr--Thr--Tyr--D--Thr--NH₂

Quite often it may be an advantage to have the amino terminal amino acidas a D-steroisomer, to protect the molecule from degradation fromaminopeptidases; alternatively or additionally, the carboxy terminalamino acid may be an amino acid amide to protect the molecule fromdegradation from carboxypeptidases. In this connection, compounds 5, 6and 7 listed above, include analogues with D--Thr as the amino terminalresidue and/or an amide derivative at the carboxy terminal.

Furthermore, it should be understood that one more of the amino acids inthe peptides may be substituted N-alkyl (e.g. (C₁ -C₄) alkyl) aminoacids instead of primary amino acids; examples include methyl and ethyl.The hydroxyl group side chains of one or more of the amino acids (Ser,Thr, Tyr) may be derivatised into an ether or ester group. Any(optionally substituted) alkyl ester or ether may be formed, such as (C₁-C₄) alkyl, aryl or aryl (C₁ -C₄) alkyl esters, ethers, thioesters andthioethers, for example phenylester, benzylether or thiophenolethylester. The presently preferred ethers are methyl, ethyl and propylethers and presently preferred esters are methyl, ethyl and propylesters.

Furthermore, it should be understood that the C-terminal amide may be analkyl amide with C₁ -C₆ (linear, branched, or cyclic), the alkyl residueitself can be substituted with single or multiple groups such ashydroxy, fluoro, etc. Similarly, the N-terminal amino group may beacetylated with carboxylic acids of C₁ -C₆ (linear, branched, or cyclic)which may be substituted with single or multiple groups such as hydroxy,fluoro, etc. Such derivations are to improve properties such assolubility, bioavailability and stability (physical, chemical,metabolic) rather than biological activity.

The hydroxyl side chains of the amino acids Ser, Thr and/or Tyr and theamido groups of the amino acids Asn and/or Gln may be substituted withdifferent carbohydrates or derivatives of carbohydrates. Carbohydratederivatives may be as discussed above.

Linear peptides useful in this invention may be prepared by any suitableprocess, such as conventional solid phase peptide synthetic techniques,see "Solid Phase Peptide Synthetic Techniques", 2nd Ed. J. M. Stewart,J. D. Young, Pierce Chemical Company, 1984, ISBN: 0-935940-03-0. Afrequently used solid phase method is the Merrifield technique. Anotherpossibility is solution phase techniques. The preferred peptide,prototype peptide T, is readily obtainable from Peptech (Europe),Hillerod, Denmark.

Cyclic peptides useful in the invention may be prepared by knowntechniques, such as, for example, described in Y. Hamada in TetrahedronLetters, 26 5155 (1985). Cyclic peptides may be established in the formof a disulphide bridge between two Cys residues and/or by reacting thecarboxy terminal amino acid residue with the amino terminal residueand/or by reacting the amino terminal residue with for example the(insert y)-carboxyl group of Glu, when Glu is at position D.

Carbohydrate derivatives may be prepared by methods known in the art.Glycosylated Peptide T is disclosed in Urge et al, Biochem. Biophys.Res. Comms. 184(2) 1125-1132 (1992), published 30 Apr. 1992, but theutility of the present invention is neither disclosed nor suggested.

Peptides useful in the invention may be administered as a composition inconjunction with a pharmaceutically acceptable carrier.

The peptides or peptide formulations may be used alone or in combinationwith any other pharmaceutically active compound, such as ananti-infective agent, for example an antibiotic and/or antiviral agentand/or antifungal agent, or another pharmaceutically active compound,such as an anti-inflammatory agent or an anti-neoplastic agent.

The peptides may be administered orally, buccally, parenterally,rectally, vaginally, by intranasal inhalation spray, by intrapulmonaryinhalation or in other ways. In particular, the peptides according tothe invention may be formulated for inhalation with spray or powder, forinjection (for example subcutaneous, intramuscular, intravenous,intra-articular or intracisternal injection), for infusion or for oraladministration and may be presented in unit dose form in ampoules ortablets or in multi-dose vials or other containers with an addedpreservative. The compositions may take such forms as suspensions,solutions, or emulsions or gels in oily or aqueous vehicles, and maycontain formulatory agents such as suspending, stabilising and/ordispersing agents. Alternatively, the active ingredient may be in powderand/or lyophilised form for direct administration or for constitutionwith a suitable vehicle (e.g. sterile, pyrogen-free water, normal salineor 5% dextrose) before use. The pharmaceutical compositions containingpeptide (s) may also contain other active ingredients such asantimicrobial agents, or preservatives.

The compositions may contain from 0.001-99% (w/v or, preferably, w/w) ofthe active material. Peptide T obtainable from Peptech (Europe) isusually formulated and packaged in a sterile manner in 5% dextrosesolution in multi-dose vials. It will be appreciated that the peptidemay be packaged in other carriers, such as saline.

Preferably, the concentration of peptide in each dose is in the order of8.5 mg/ml for subcutaneous injection in one ml doses.

The compositions are administered in therapeutically or prophylacticeffective doses, i.e. 0.05-10000 mg of peptide per day, in particular5-1000 mg per day. Very large doses may be used as the peptide accordingto the invention is non-toxic. However, normally this is not required.The dose administered daily of course depends on the degree of controlrequired.

For administration by injection or infusion of the composition, thedaily dosage, as employed for treatment of adults of approximately 70 kgof body weight, will often range from 0.2 mg to 20 mg of active materialwhich may be administered in the form of 1 to 4 doses over each day,such dosage ranges depending upon the route of administration and thecondition of the patient.

Composition as described above may be prepared by mixing or otherwisebringing into association the ingredients.

Presently the principal therapeutic used in the treatment of Crohnsdisease is the steroid prednisone. In addition, the non-steroidalanti-inflammatory agents 5 ASA and 4 ASA are also commonly used. Giventhe usefulness of Peptide T and its analogues in treating Crohns diseaseit is believed that treatment involving Peptide T and its analogues maybe a useful adjunct to therapy involving the use of steroidal andnon-steroidal anti-inflammatories. Such as adjunct therapy may allow areduction in the levels of administration of the commonly usedanti-inflammatory agents. It is intended that such adjunct therapy iswithin the scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in more detail with reference to thefollowing Examples and accompanying drawings in which:

FIG. 1 shows the effects of peptide T on total WBC counts;

FIG. 2 shows the effects of Peptide T on TNBS colitis-associated changesin body weight;

FIG. 3 shows the effects of Peptide T on the severity of mucosal injury;

FIG. 4 shows the effects of Peptide T on the severity of colonicadhesions;

FIG. 5 shows the effects of Peptide T on colonic weight/length ratio;

FIG. 6 shows the effects of Peptide T on degree of diarrhoea; and

FIG. 7 shows the effects of Peptide T on colonic myeloperoxidaseactivity.

In order that the nature of the present invention may be more clearlyunderstood preferred forms thereof will now be described with referenceto the following examples.

EXAMPLE

A. Purpose of Study

To examine the potential therapeutic efficacy and mechanisms of actionof Peptide T in the treatment of TNBS colitis in rats during both itsacute/subacute (0 to 2 week) and combined acute, subacute and chronic (0to 4 week) phases.

B. Summary of Methods

Male Sprague-Dawley rats, weighing 265-315 g were sedated with an i.p.injection of Innovar-Vet (fentanyl+droperidol) at a dose of 0.03 ml/100g body weight and received an intrarectal instillation of either 0.8 ml30 mg TNBS in 30% Ethanol (TNBS colitis animals) or normal saline(control/no colitis animals). On the day following i.r. instillations,control animals were treated with a s.c. injection of vehicle and TNBScolitis animals were treated with the s.c. injection of vehicle,prednisone (5 mg/kg), or Peptide T (0.1, 1.0, 10 mg/kg). Treatment wascontinued on a once daily basis for the following 14 or 28 days.

On day 14 (2 week series) or 28 (4 week series), animals were weighedand anaesthetised with pentobarbital. A cardiac puncture was performedto obtain a sample of peripheral blood for the determination of totalwhite blood cell count (WBC) using a coulter counter, and differentialcount. A midline laparotomy was then performed and the colon exposed andexcised. The colon was then opened longitudinally and rinsed clear offascal material. The severity of colonic mucosal injury, diarrhoea, andadhesions was then scored by an observer unaware of the treatment groupof the animals using the attached criteria. The length (in cm) andweight of each colonic segment was then determined to allow thedetermination of the colonic weight/length ratio (as an index ofintramural edema and/or fibrosis). Samples of tissue were then taken forbiochemical determination of tissue myeloperoxidase (MPO) activity, asan index of granulocyte accumulation using standard biochemicaltechniques. Samples of tissue were also taken and fixed for subsequentprocessing for histopathological examination.

Differences between the different treatment groups were analysed usingeither one way analysis of variance (body weight, WBC counts, colonicweight/length ratio, MOP activity) or the non-parametric equivalentKruskall-Wallis test (semiquantitive grading of severity of mucosalinjury, adhesions, or diarrhoea). Significance of differences betweenindividual pairs of treatment groups were then assessed using post hocTukey's test for parametric data and Dunn's multiple comparison test fornon-parametric data.

    ______________________________________                                        CRITERIA FOR SEMI-QUANTITATIVE GRADING                                        OF MACROSCOPIC INJURY                                                         DEGREE AND TYPE OF INJURY   SCORE                                             ______________________________________                                        Normal appearance           0                                                 Focal hyperemia, no ulcers  1                                                 Single site of limited (2-5 mm) ulceration without                                                        2                                                 inflammation                                                                  Single site of limited (2-5 mm) ulceration with                                                           3                                                 inflammation                                                                  Two or more sites of discrete ulceration or                                                               4                                                 inflammation                                                                  Major site of ulceration or inflammation extending                                                        5                                                 1-2 cm along length of colon                                                  Major site of ulceration or inflammation extending                                                        6-10                                              >2 cm along length of colon (increased by 1 for                               each additional cm of damage                                                  ADHESION SCORE                                                                No adhesions                0                                                 Limited adhesion of pericolic fat or 1-2 loops of                                                         1                                                 small bowel                                                                   Adhesion to several (3-5) loops of small bowel +/-                                                        2                                                 pericolic fat                                                                 Extensive adhesion of multiple loops of bowel                                                             3                                                 ______________________________________                                    

C. Summary of Results of 2 Week Series Examining the Efficacy of PeptideT in the Treatment of TNBS Colitis

C.i Effects of Peptide T on Total WBC Counts

As can be seen in FIG. 1, in animals with TNBS-induced colitis receivingonce daily s.c. injections of vehicle, the total WBC counts, wereapproximately double those observed in control (no colitis) animalsreceiving vehicle. Once daily s.c. injections for 2 weeks withprednisone 5 mg/kg, Peptide T 0.1 mg/kg, Peptide T 1.0 mg/kg, or PeptideT 10 mg/kg, all led to reductions in total WBC counts in animals withTNBs colitis when compared to animals with colitis receiving vehicle.Although these reductions in WBC counts did not quite attain statisticalsignificance (p<0.05), all of them showed p values of 0.06-0.07 vs TNBscolitis animals receiving vehicle.

C.ii Effects of peptide T on TNBS Colitis-Associated Changes in BodyWeight

FIGS. 2 shows the initial (i.e. prior to colitis induction) and finalbody weights of animals in each different treatment group 2 weeks afterinitiation of TNBS colitis. As can be seen, control animals (i.e. thosewith no colitis receiving daily injections of vehicle) experienced asignificant (p<0.05) weight gain over the 2 week period. In contrast,animals with TNBs colitis receiving vehicle failed to gain significantbody weight during the 2 week evolution of the colitis. Interestingly,treatment with either the prednisone or Peptide T at any of the 3 dosestended to cause increased weight gains in animals with colitis, withthis becoming significant (p<0.05) in animals receiving prednisone andPeptide T at the 10 mg/kg dose and approaching significance (p values of0.06 to 0.08) in animals receiving Peptide T at 0.1 or 1.0 mg/kg!.

C.iii Effects of Peptide T on Parameters of Colonic Injury

FIGS. 3 to 7 show results for various indices of colonic injury/colitis.As can be seen in FIG. 3, none of the treatments attenuated the severityof mucosal injury as assessed using an established semiquantitativegrading scale. There was a subtle suggestion however, that Peptide T ata dose of 10 mg/kg may have marginally reduced the severity of mucosalinjury. In a similar fashion, none of the treatments significantlyreduced the severity of colonic adhesions (FIG. 4) developing in animalswith TNBS colitis, although there was a general trend towards reductionof adhesions in animals treated with prednisone or peptide T 0.1 or 10mg/kg. Virtually identical patterns were observed using colonicweight/length ratio (FIG. 5) and colonic myeloperoxidase activity (FIG.7) as indices of colonic edema and granulocyte accumulationrespectively. Despite these subtle trends suggesting a reduction in theseverity of TNBs colitis in animals treated with prednisone or Peptide T0.1 or 10 mg/kg, virtually all animals in the colitis groups (treatedand untreated) demonstrated a similar degree of diarrhoea (FIG. 6).

C.iv Summary of Results/Conclusions for 2 Week Series

The results of assessments performed 2 weeks following induction of TNBscolitis (i.e. during the acute and subacute phase of the colitis), seemsto indicate that Peptide T at any of the 3 doses (0.1, 1.0, 10 mg/kg)appears comparable to prednisone in reducing the severity of theleukocytosis and failure to thrive/lack of weight gain associated withthe development of TNBS colitis in rats. These results are consistentwith the hypothesis that Peptide T is reducing the constitutional orsystemic manifestations of the colitis.

4 Week Results

By the 4 week time point the animals with TNBs colitis receiving vehiclewere largely recovered and it appeared that the colitis had resolveditself spontaneously.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the spirit or scope ofthe invention as broadly described. The present embodiments are,therefore, to be considered in all respects as illustrative and notrestrictive.

    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 8                                                  (2) INFORMATION FOR SEQ ID NO:1:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                       AlaSerThrThrThrAsnTyrThr                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:2:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..10                                                           (D) OTHER INFORMATION: /product="OTHER"                                       /note= "Xaa at position 1 = C or absent (abs), 2 or 3 =                       A,G,V,S,T or abs, 4=S,T or abs, 5 = S,T,N,E,R,I,L or abs,                     6 = S,T,D or abs, 7 = T,S,N,R,Q,K,W or abs, 8 =                               Y,F,W,L,M,I or abs, 9 = T,R,G,M,M(0),C,T,G or abs, and                        10 = C or absent"                                                             (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                       XaaXaaXaaXaaXaaXaaXaaXaaXaaXaa                                                1510                                                                          (2) INFORMATION FOR SEQ ID NO:3:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                       ThrThrAsnTyrThr                                                               15                                                                            (2) INFORMATION FOR SEQ ID NO:4:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Peptide                                                         (B) LOCATION: 1..8                                                            (D) OTHER INFORMATION: /product="OTHER"                                       /note= "Xaa at position 1 is Ala or D-Ala and Xaa at                          position 8 is Met, Thr or Thr-amide"                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                       XaaSerThrThrThrAsnTyrXaa                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:5:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                       SerThrThrThrAsnTyr                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:6:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                       AlaSerThrThrThrAsnTyrThr                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:7:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                       ThrAspAsnTyrThr                                                               15                                                                            (2) INFORMATION FOR SEQ ID NO:8:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: peptide                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                       ThrThrSerTyrThr                                                               15                                                                            __________________________________________________________________________

We claim:
 1. A method of treating Crohn's Disease in a subjectcomprising administering to the subject a therapeutic amount of a linearor cyclic peptide of General Formula 2:

    X--Ser--Thr--Thr--Thr--Asn--Tyr--Y (General Formula 2) (SEQ ID NO: 4)

wherein X is an amino acid terminal residue selected from Ala and D--Alaand Y is a carboxy terminal residue selected from Met, Thr andThr-amide, or a pharmaceutically acceptable salt thereof.
 2. A method asclaimed in claim 1 in which the peptide is administered as a compositionin conjunction with a pharmaceutically acceptable carrier.
 3. A methodas claimed in claim 1 in which the peptide is linear.
 4. A method oftreating Crohn's Disease in a subject comprising administering to thesubject a therapeutic amount of a peptide selected from the groupconsisting of:1. D--Ala--Ser--Thr--Thr--Thr--Asn--Tyr--Thr--NH₂ 2.Ala--Ser--Thr--Thr--Thr--Asn--Tyr--Thr (SEQ ID NO: 6) 3.D--Ala--Ser--Thr--Thr--Thr--Asn--Tyr--Thr 4.D--Ala--Ala--Ser--Ser--Ser--Asn--Tyr--Met
 5. Thr--Asp--Asn--Tyr--Thr(SEQ ID NO: 7)
 6. Thr--Thr--Ser--Tyr--Thr (SEQ ID NO: 8) 7.Thr--Thr--Asn--Tyr--Thr (SEQ ID NO: 3)
 8. D--Thr--Thr--Tyr--D--Thr 9.D--Ala--Ser--D--Thr--Thr--D--Thr--Asn--Tyr--D--Thr--NH₂ 10.D--Ser--Ser--D--Thr--Thr--D--Thr--Thr--Tyr--D--Thr--NH₂.
 5. A method asclaimed in any one of claims 1 to 4 in which one more of the amino acidsin the peptide is a substituted N-alkyl amino acid.
 6. A method asclaimed in claim 5, wherein said alkyl group contains 1 to 4 carbonatoms.
 7. A method as claimed in any one of claims 1 to 4 in which thehydroxyl group side chains of one or more of the amino acids Ser, Thr,and/or Tyr is derivatised into an ether or ester group.